The long-term objectives of the proposed research are to initiate the first systematic study of cognitive and behavioral consequences of Barth syndrome, and to thereby examine potential associations between brain function and the specific biochemical pathways disrupted in Barth syndrome. The pathways implicated in this research are ones that may be modified by diet (linoleic acid enriched fats, cholesterol, and phospholipid). Thus the health relatedness of this project concerns potential benefits to persons with Barth syndrome, and to the general population. The research findings may enhance identification of, and intervention for, learning difficulties that may occur with Barth syndrome. Moreover, associate a Mendelian metabolic disorder with discrete learning deficits may reveal presently unknown metabolic or nutritional influences on brain development. Barth syndrome is an X-linked recessive metabolic disorder characterized by short stature, cardioskeletal myopathy, cyclic neutropenia, increased excretion of 3-methylglutaconic acid in the urine, and moderate hypocholesterolemia. In 1991, Dr. Richard Kelley, co-investigator, and colleagues reported the discovery of a unique biochemical abnormalities associated with the disorder (3-methylglutaconic aciduria). DNA studies have since indicated a mutation of the G4.5 gene located at Xq28 (e.g., Bolhuis et al., 1991). The G4.5 gene functions as a fatty acyl transferase in the synthesis of cardiolipin; Barth syndrome cells and tissues are very deficient in cardiolipin. This makes Barth syndrome the first known defect in the biosynthesis of cardiolipin, an important structural lipid in the mitochondrial inner membrane and other cellular membranes involved in tissue development and cellular function. Despite advances into the biochemical and diagnostic features of Barth syndrome, the systematic study of a cognitive phenotype is limited to a preliminary study by the investigators of the proposed research. Thus the primary aims of the proposed study are to systematically examine evidence the cognitive and behavioral phenotype of Barth syndrome during the primary school age years, to delineate developmental factors that are potential targets for early intervention, and to identify possible biological correlates of the cognitive features that are identified. Methods will involve cognitive assessment of children with Barth syndrome and matched peers, paired comparisons, and correlation analyses.